Ciliopathy

Ciliopathies are a group of genetically diverse disorders caused by defects in the structure or function of the primary cilium, a highly specialized and evolutionarily conserved organelle found in nearly all eukaryotic cells.^[1] The primary cilium plays a central role in regulating signal transduction and making it essential for numerous developmental and physiological processes.^[2]

Eukaryotic cilium

Because of the widespread presence of primary cilia in different tissues, dysfunction can lead to a broad spectrum of clinical features. Syndromic ciliopathies, such as Bardet-Biedl syndrome (BBS), typically involve multiple organ systems, including the retina, kidneys, central nervous system, and skeletal system^[1] These manifestations highlight the importance of cilia in embryonic development, sensory perception, and tissue homeostasis.^[3]

The genetic basis of ciliopathies is complex, with significant allelic heterogeneity and pleiotropy, meaning the same gene may cause different disorders, while different mutations can result in overlapping clinical features. Such variability makes genotype-phenotype correlation particularly challenging.^[1][4] Advances in genetic technologies, such as expression quantitative trait locus (eQTL) analysis, are helping to clarify the molecular mechanisms that drive these diseases. While progress has been made in understanding ciliogenesis and the molecular pathways involved, therapeutic development is still in its early stages. Gene therapy and other molecular approaches hold promise but must overcome several scientific and technical barriers before they can be widely implemented.^[1]

Primary cilia, which are found on nearly all cell types, function as sensory structures and integrate signals from the environment. When these functions are compromised, it can lead to serious diseases such as polycystic kidney disease, Bardet-Biedl syndrome, Joubert syndrome, and primary ciliary dyskinesia.^[3] Even proteins that are not directly localized to the cilia, such as XPNPEP3—which is associated with mitochondria—can cause ciliopathies by affecting proteins essential to ciliary function.^[1]

In the 1990s, important advances were made in understanding the significance of cilia.^[5] Ciliary defects were identified in genetic disorders such as nephronophthisis and primary ciliary dyskinesia, and it became clear that abnormalities in ciliary structure and transport mechanisms could explain the broad, multi-organ effects observed in patients with ciliopathies.^[1][3]

Although our understanding of the role of cilia in developmental biology and disease has grown considerably over the past decade, the mechanisms behind their function in many tissues remain incompletely described. Current research is particularly focused on how disruptions in intraflagellar transport, signal reception, and cilia-associated protein complexes contribute to the pathogenesis of ciliopathies.^[3][4]

Signs and symptoms

Since cilia are found in many different types of cells and organs, the body will be affected if there is an error or dysfunction. When the cilia do not function properly, multiple symptoms commonly occur, such as:^[1]

• Retinal degeneration^[1]
• Obesity^[1]
• Renal dysfunction^[1]
• Hepatic abnormalities^[1]
• Diabetes^[1]
• Hypertension^[1]
• Polydactyly^[1]
• Hearing impairment^[1]
• Skeletal anomalies^[1]
• Congenital heart defects^[1]
• Anosmia^[1]
• Abnormal heart size^[1]
• Infertility^[1]
• Intellectual disabilitites^[1]

Although significant progress has been made in understanding cilia and their role in disease, many aspects remain unexplored. Ongoing research is crucial to uncover the underlying mechanisms of ciliopathies and to develop effective therapeutic strategies.^[6][7]

List of ciliopathies

Primary ciliopathy	OMIM	Clinical manifestations	Gene(s)	Systems/organs affected
Diseases or syndromes		Clinical features	Associated genes
Alstrom syndrome[8]	203800	Obesity, retinitis pigmentosa, diabetes mellitus, hypothyroidism, hypogonadism, skeletal dysplasia, cardiomyopathy, pulmonary fibrosis[8]	ALMS1[8]	hearing loss, vision loss, liver[9]
Bardet-Biedl syndrome[8]	209900	Obesity, polydactyly, developmental delay, retinitis pigmentosa, renal anomalies, anosmia, hypogonadism, congenital heart disease[8]	ARL6, BBS1-12, CEP290, MKKS, MKS1, MKS3, SDCCAG8, TRIM32, WDPCP[8]	Skeletal anomaly, kidney, vision loss[10]
Ellis van Creveld syndrome[8]	225500	Chondrodystrophy, polydactyly, ectodermal dysplasia, congenital heart disease[8]	EVC, EVC2[8]	Skeletal anomaly, skin, teeth and heart[11]
Jeune syndrome[8]	208500	Thoracic cage deformities, renal cysts, retinitis pigmentosa, skeletal dysplasia, polydactyly[8]	DYNC2H1, IFT80, IFT139, IFT140, IFT144, WDR35[8]	Brain, retina, lungs, liver, pancreas and kidneys[12].
Joubert syndrome[8]	213300	Central nervous system anomalies, developmental delay, ataxia, retinitis pigmentosa, polydactyly, cleft lip, cleft palate[8]	ATXN10, AHI1, ARL13B, C5ORF42, CC2D2A, CEP41, CEP290, CORS2, INPP5E, JBTS1, JBTS3, JBTS4, KIF7, NPHP1, NPHP3, RPGRIP1L, TCTN1, TCTN2, TMEM67, TMEM138, TMEM216, TMEM237[8]	Rentia, kidney, and liver[13]
Meckel-Gruber syndrome[8]	249000	Renal cysts, polydactyly, developmental delay, CNS anomalies, congenital heart disease, cleft lip, cleft palate[8]	B9D1, B9D2, CC2D2A, CEP290, MKS1-6, MKKS, NPHP3, RPGRIP1L, TCTN2, TMEM67, TMEM216[8]	Skeletal anomaly, kidneys, liver, birth defect and heart[14]
Nephronophthisis[8]	256100	Renal cysts, interstitial nephritis, hepatic fibrosis, retinitis pigmentosa[8]	ALMS1, ATXN10, CEP290, GLIS2, IFT139, INVS, NEK8, NPHP1-11, TCTN2, TTC21B, TTC8, WDR19, XPNPEP3[8]	Kidney[15]
Orofaciodigital syndrome type 1[8]	311200	Polydactyly, syndactyly, cleft lip, cleft palate, brain anomalies, developmental delay, renal cysts[8]	OFD1[8]	Face[16]
Polycystic kidney disease[8]	173900	Early onset renal cysts, hepatic fibrosis[8]	PKHD1[8]	Kidney[17]

Pathophysiology

Cilia are microscopic, hair-like structures that extend from the surface of nearly all mammalian cells. They are composed of complex protein structures and play a crucial role in various cellular functions, including movement and signal transduction.^[18]

Cilia are categorized into two main structural subtypes based on the organization of their microtubule axoneme: motile and non-motile (primary) cilia. Motile cilia are typically structured in a 9+2 arrangement, consisting of nine outer microtubule doublets surrounding a central pair of microtubules.^[18] This structure is specialized for movement, enabling functions such as fluid transport across epithelial surfaces, cell motility, and propulsion of spermatozoa.^[19][20]

In contrast, primary (non-motile) cilia display a 9+0 arrangement, where nine outer microtubule doublets are present without a central pair. Rather than generating movement, these cilia serve as cellular antennae, playing crucial roles in sensory perception, intracellular signaling, and regulation of developmental pathways, including organogenesis.^[18] Primary cilia function mainly as sensory organelles, involved in signal transduction and the maintenance of cellular homeostasis.^[21]

This structural distinction is fundamental to understanding the diverse biological functions and pathologies associated with ciliopathies.^[1]

Genetics

Ciliopathies are genetically heterogeneous disorders that arise due to mutations in genes associated with the structure and function of cilia. A unique feature of these conditions is that the same gene can be involved in different diseases, and that different genes can lead to similar phenotypes.^[22] For example, mutations in certain genes have been linked to both Meckel–Gruber syndrome and Bardet–Biedl syndrome, and in some patients carrying mutations in both, combined phenotypes have been observed that do not occur in either condition alone.^[1]

Because ciliopathy genes often function within interconnected developmental pathways, systems biologists are seeking to define gene modules—co-regulated sets of genes that drive specific biological outcomes.^[1][4]

Furthermore, significant phenotypic overlap has been documented among different ciliopathies, largely due to the fact that many of the involved genes affect primary cilia function.^[22] As a result, the same mutation can lead to different clinical presentations, suggesting that genetic modifiers (i.e., other genes that influence disease expression) play an important role in determining disease severity and organ involvement.^[3][7] As of 2017, 187 genes had been confirmed to be directly associated with ciliopathies, with an additional 241 candidate genes still under investigation.^[3]

This genetic complexity makes molecular diagnosis both challenging and essential. For inherited ciliopathies such as autosomal dominant and autosomal recessive polycystic kidney disease (ADPKD and ARPKD), traditional methods like linkage analysis and targeted mutation screening have been used.^[3] Modern approaches such as gene panels, exome sequencing, and whole genome sequencing are increasingly replacing traditional methods, as they enable the identification of both known and rare mutations and can detect heterozygous carriers in recessive disorders.^[3] These methods allow for broader detection of both common and rare mutations and are particularly useful for identifying heterozygous carriers in recessive ciliopathies. By providing a more comprehensive genetic profile, these tools enhance diagnostic precision and support the identification of novel ciliopathy- associated genes.^[1][3]

A classic example of a genetically defined ciliopathy is ADPKD, which is caused by mutations in PKD1 and PKD2, encoding polycystin-1 and -2, respectively. These proteins are essential for the mechanosensory function of cilia in the renal epithelium. Mutations result in defective signaling and cyst formation, which can eventually lead to kidney failure.^[1][4][7]

History

The discovery of cilia marked a pivotal moment in biological science. In the 1670s, Dutch microscopist Antonie van Leeuwenhoek described microscopic "animalcules" in rainwater, observing tiny, moving projections on their surfaces—structures that are now recognized as cilia. This was the first recorded observation of cellular appendages involved in locomotion and environmental sensing.^[23]

Despite early recognition, the functional importance of cilia remained underappreciated for centuries. Non-motile, or primary cilia, were first described in 1898, but were largely dismissed as vestigial structures without biological significance.^[3] It was not until the advent of advanced microscopy and molecular genetics in the late 20th and early 21st centuries that the essential roles of cilia in development and disease became clear.^[3][23] Today, primary cilia are understood as sensory organelles that coordinate diverse signaling pathways such as Hedgehog and Wnt, and are critical for tissue patterning, cellular differentiation, and organ development.^[1] Cilia function as cellular “antennae,” detecting mechanical, chemical, and thermal cues from the environment.^[3][23]

The modern era of ciliopathy research has been driven by advances in mammalian genetics. These have enabled the identification of mutations in cilia-related genes that underlie a wide spectrum of genetic disorders, now collectively referred to as ciliopathies. These include autosomal dominant and recessive polycystic kidney disease, nephronophthisis, Bardet–Biedl syndrome, Joubert syndrome, and others. The overlapping phenotypes of these diseases reflect the shared molecular architecture of cilia and their conserved roles across organ systems.^[1] Foundational work in embryology by scientists such as Karl Ernst von Baer laid the conceptual groundwork for modern developmental biology. Although von Baer did not explicitly describe cilia, his meticulous observations of embryonic tissues likely included ciliated structures. His legacy continues to influence current research into the roles of cilia in early development, particularly in establishing left-right asymmetry and proper organ positioning.^[1][23]